Genetic structure of co-morbidity between frailty and rheumatoid arthritis: a genome-wide association analysis

doi:10.12307/2026.110

Abstract

Abstract: BACKGROUND: Frailty and rheumatoid arthritis are both chronic diseases that seriously impact health. With the accelerating aging population in China, the prevalence of chronic diseases such as frailty and rheumatoid arthritis continues to rise. Existing studies have suggested an association between the two, but their shared genetic basis is still unclear. Therefore, further in-depth exploration of the comorbid genetic structure of frailty and rheumatoid arthritis is necessary to provide insights into co-morbid prevention and treatment of the two diseases.
OBJECTIVE: To explore the possible shared genetic structure and potential biological links between frailty and rheumatoid arthritis, and to provide a scientific basis for co-morbidity prevention and treatment.
METHODS: We utilized whole-genome sequencing data for frailty from the GWAS Catalog database and rheumatoid arthritis data from the FinnGen R11. Linkage disequilibrium score regression analysis, Bayesian analysis, and stratified linkage disequilibrium score regression analysis were employed to assess the genetic correlation between frailty and rheumatoid arthritis. Multi-trait analysis and cross-trait meta-analysis were used to identify shared risk single nucleotide polymorphisms. Gene and gene-set association analysis tools and stratified linkage disequilibrium score regression analysis were applied for tissue-specific enrichment analysis. Finally, two-sample Mendelian randomization analysis based on generalized summary data was conducted to investigate potential bidirectional causal relationships between frailty and rheumatoid arthritis.
RESULTS AND CONCLUSION: Frailty and rheumatoid arthritis exhibited significant positive genetic correlation (rg=0.28, P=4.54×10-35), particularly in specific loci at 6p21.32-21.33 (chr6:31571218-33236497). Through integrating multiple analytical methods, we successfully identified four single nucleotide polymorphisms (rs111294540, rs560607175, rs9277362, rs144112342) that shared risk between frailty and rheumatoid arthritis, located in the HLA-DQA1, HLA-DPA1, and TAP2 genes. Functional element analysis revealed 12 significant elements associated with both frailty and rheumatoid arthritis. Combined with gene expression data, tissue-specific enrichment analysis showed that single nucleotide polymorphisms associated with both frailty and rheumatoid arthritis were specifically enriched in the spleen. Furthermore, Mendelian randomization validated the bidirectional causal relationship between frailty and rheumatoid arthritis. This study elucidated the shared genetic basis between frailty and rheumatoid arthritis, revealing significant genetic correlation and common risk genes for both diseases, and validating their bidirectional causal relationship. These findings provide a reference for the future exploration of the comorbidity mechanisms and therapeutic targets for the two conditions. Although this research utilized data from European populations, it holds valuable implications for the prevention and treatment of chronic diseases in the context of the increasingly aging population in China.

Key words: rheumatoid arthritis, frailty, genome-wide association study, shared genetic structure, co-morbidity mechanism, therapeutic target

CLC Number:

Han Jie, Yao Guojun, Huang Yebao, Xu Zhiwei, Shao Weigang, Shang Kebin, Wu Yachao, Liao Zhen. Genetic structure of co-morbidity between frailty and rheumatoid arthritis: a genome-wide association analysis[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(17): 4548-4556.

Figures/Tables 5

2.1 衰弱与类风湿性关节炎之间的遗传相关性此次研究采用了LDSC方法，利用SNPs间的连锁不平衡，来评估两种性状间的遗传联系。在不受截距约束的情况下，衰弱的SNPs遗传力估计为11.72%，类风湿性关节炎的SNPs遗传力估计为4.20%。随后，采用双变量LDSC方法估计了衰弱与类风湿性关节炎之间的遗传相关性。结果显示，衰弱与类风湿性关节炎之间存在显著的遗传正相关性(rg=0.28，P=4.54×10-35)。在假设不存在群体分层的情况下，当LDSC截距受约束时，结果仍显著(rg=0.37，P=3.38×10-15)。见表1。 2.2 衰弱与类风湿性关节炎之间的局部遗传相关性应用ρ-HESS方法确定了衰弱与类风湿性关节炎之间的显著局部遗传相关性。经过多重检验校正后(P < 0.05/1 703)，在6p21.32-21.33(chr6:31571218-33236497)这两个特定区域，发现衰弱与类风湿性关节炎之间存在显著的局部相关性，见表2及图2。 2.3 分区遗传相关性与衰弱部分遗传相关的SNPs在96个功能元件中，有30个功能元件中显示出显著富集，其中最显著的功能元件为GERP.NSL2_0(enrichment=1.962，P=2.88×10-17)。与类风湿性关节炎相关的SNPs在96功能元件中，有27个类别中表现出显著富集，最显著是SuperEnhancer_HniszL2_0(enrichment=3.703，P=3.85×10-11)。有12个功能类别同时与衰弱和类风湿性关节显著相关，见图3。 2.4 跨性状GWAS荟萃分析使用MTAG和CPASSO进行的跨性状分析共识别出11个达到全基因组显著性的共享独立SNPs。在对6p21.32-21.33区域SNPs进行筛选时，排除在衰弱与类风湿性关节炎的GWAS中同时显著的SNPs，或与同时显著的SNPs存在连锁(连锁不平衡 r2?≥?0.01)的SNPs后，最终确认有4个SNPs与衰弱和类风湿性关节炎均相关，见表3。SNP rs111294540、rs560607175定位于HLA-DQA1基因，SNP rs9277362定位于HLA-DPA1基因，SNP rs144112342定位于TAP2基因。 2.5 组织特异性富集分析使用MAGMA进行组织特异性富集分析，结果显示：与衰弱相关的SNPs在9个不同的脑区中特异性富集，其中特异性富集最显著在额叶皮质(BA9)。而类风湿性关节炎则在18个不同的组织中特异性富集，其中特异性富集最显著在脾脏，见图4。此外，进一步使用S-LDSC分析衰弱和类风湿性关节炎在组织水平上的SNPs遗传力富集。结果显示，与衰弱相关的SNPs在12个不同大脑组织及脾脏中表现出明显的富集，其中特异性富集最显著在前扣带皮质(BA24)。与类风湿性关节炎相关的SNPs在5个不同组织中表现出明显的富集，其中特异性富"

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